This project aims to discover and develop a new therapy for major depressive disorder (MDD), which affects 40 million people annually, profoundly reducing quality of life. Current treatments offer relief to only half of patients, and then only after weeks of treatment and with a high prevalence of adverse effects. Agonists of the delta-opioid receptor are antidepressant with rapid onset in rodents, and are analgesic and anxiolytic. They may offer a valuable new approach to treating MDD and in particular the sizeable fraction of MDD patients who also suffer anxiety or chronic pain. Unfortunately, delta-opioid agonists also cause convulsions in rodents and primates, which have thwarted drug development efforts to date; they also display transient efficacy limited by tolerance. However, recent data suggest that therapeutic, tolerizing, and convulsive effects of the delta-opioid receptor activation can be separated by a special class of agonist called biased ligands, which selectively engage only a subset of the receptor signals normally stimulated by standard agonists. This project is based on a novel delta-opioid receptor biased ligand that potently and robustly activates therapeutic G protein signaling, but unlike standard agonists does not engage p-arrestin, which promotes tolerance and convulsions. This molecule is selective for the delta-opioid receptor and has characteristics appropriate for optimization into a new drug molecule. Through partnership with the NIH Blueprint for Neuroscience Grand Challenge, this project aims to engage iterative cycles of medicinal chemistry and biological testing in vitro and in vivo to derive a candidate drug with appropriate efficacy and safety to permit filing an Investigational New Drug application with the U.S. FDA and a Phase I clinical study to test pharmacokinetics, safety, and tolerability of the compound in normal volunteers. Successful completion of this project will deliver a compound with compelling preclinical proof of concept for a rapid onset antidepressant, potentially with anxiolytic and analgesic properties, with early clinical data to support testing in patients. This data will be ideal to attract further funding or partnership for further clinical trials and a New Drug Application to deliver a valuable new therapy to the millions of patients suffering from MDD.